Initial Characterization of A Mouse Model of Severe Asthma

Abstract

Severe asthma patients have symptoms that are frequently hard to manage with low dose inhaled corticosteroids (ICS) and often need additional high dose oral steroids. Neutrophilic airway inflammation is also associated with corticosteroid insensitivity in this population. We have investigated the effect of inhaled and oral steroids, a p38 MAPK inhibitor and an anti-mouse IL-17 monoclonal antibody (mAb) in a mouse severe asthma model. Methods BALB/c mice were sensitised with house dust mite (HDM, 100µg s.c.) emulsified in Complete Freunds Adjuvant (CFA) and 14 days later challenged with 100µg HDM intra nasally. Mice were dosed with steroid (Budesonide 0.1, 0.3, 1mg/kg i.n. or Dexamethasone 0.3, 1, 3mg/kg p.o.), or the p38 MAPK inhibitor BIRB-796 (3mg/kg, p.o.), or anti-IL-17 mAb (200µg/mouse, s.c.), or vehicle prior to and/or following HDM-challenge. The lungs were lavaged and differential cell numbers determined. Results HDM-challenge caused a significant increase in both neutrophils and eosinophils in the lung lavage. All Budesonide doses failed to inhibit the neutrophilia and only the maximum dose (1mg/kg) inhibited eosinophilia (p<0.05, 47% inhibition). Only the highest dose of Dexamethasone (3mg/kg) inhibited both the neutrophilia (p<0.0001, 81% inhibition) and eosinophilia (p<0.0001, 85% inhibition). BIRB-796 did not inhibit either the neutrophilia and eosinophilia. However, the anti-IL-17 mAb inhibited the neutrophilia (p<0.0001, 46% inhibition), but not the eosinophilia. In summary, the CFA/HDM severe asthma model is insensitive to ICS but sensitive to high doses of oral steroid, thus mimicking phenotypes of human disease. In addition, the neutrophilic inflammation is inhibited with anti-IL-17 mAb treatment. The model may be useful to investigate potential mechanisms. Funded by Argenta